The object of this work is to test the hypothesis that general anesthetics act at the molecular level by perturbing the structure of the lipid region of some membrane and hence compromising the function of a membrane protein vital to neuronal excitability. This hypothesis is a specific interpretation of the critical volume hypothesis arrived at by studies of pressure reversal of anesthesia. The underlying theme is measurement of anesthetic induced changes in membrane structure in parallel with measurements of functional changes. The first phase of the research is directed towards simple, characterized lipid bilayers in order that underlying general principles may be elucidated and that, by comparing the effects of anesthetics and pressure on a variety of such systems with their effects on whole animals and nerves, some deductions about the real site of action may be made. Methods will include ionophore facilitated cation permeability measurements and electron spin resonance studies of structural changes using nitroxyl-labeled lipids. The second phase of the research is directed at an isolated excitable membrane, the cholinergic receptor containing membrane of certain electric fish. Structural and functional studies will again be carried out in parallel. Electron spin resonance techniques will be used to probe the anesthetic induced changes in membrane lipid structure which accompany certain functional changes. The chemically stimulated sodium ionophore mediated efflux from sealed microsacs from the electric membrane, and the binding of agonists and of antagonists to membrane fragments in the presence and absence of anesthetics and pressure will be studied.